The main histopathological characteristics of Alzheimer's disease (“AD”) are the presence of neuritic plaques and tangles combined with associated inflammation in the brain. It is known that plaques are composed mainly of deposited (or insoluble in aqueous solution) fibrillar forms of the A-beta (“A-beta”) peptide. The formation of fully fibrillar aggregated A-beta peptide is a complex process that is initiated by the cleavage of the amyloid precursor protein (“APP”). After cleavage of APP, the monomeric form of A-beta can associate with other monomers, presumably through hydrophobic interactions and/or domain swapping, to form dimers, trimers and higher order oligomers. Oligomers of A-beta can further associate to form protofibrils and eventual fibrils, which is the main constituent of neuritic plaques.
Soluble A-beta oligomers have also been implicated in neuronal dysfunction associated with AD. In fact, animal models suggest that simply lowering the amount of soluble A-beta peptide, without affecting the levels of A-beta in plaques, may be sufficient to improve cognitive function.
Presently, the only definitive method of AD diagnosis is postmortem examination of the brain or tissue for the presence of plaques and tangles. Currently, AD diagnosis is achieved using simple cognitive tests designed to test a patient's mental capacity such as, for example, the ADAS-cog (Alzheimer's disease assessment scale—cognitive subscale) or MMSE (Mini-mental state examination). The subjective nature and inherent patient variability is a major shortcoming of diagnosing AD by such means. The inability to diagnose AD in a living patient presents a formidable challenge for pharmaceutical companies that aim to test putative therapeutics to slow or halt AD pathogenesis by acting on one or more species of A-beta. Because A-beta binders are needed for diagnostic and/or therapeutic applications, significant needs exist for methods of assaying the ability of agents to bind to various species of A-beta.